A Translational Program of BDNF Gene Delivery in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是最常见的神经退行性疾病，仅在美国就有500万人受到影响。这份U授权申请 将支持向FDA提交脑源性神经营养因子(BDNF)基因治疗AD的研究新药(IND)申请。我们已经在小鼠、大鼠和非人类灵长类动物上完成了概念验证研究，表明BDNF可以防止内嗅皮层神经细胞丢失，增强突触标志物，逆转与AD相关的分子和生化特征，并改善学习和记忆。这些效应延伸到海马体，从而治疗大脑的关键记忆回路。重要的是，这种方法为目前正在开发的淀粉样蛋白修饰疗法提供了一种亟需的替代方案，如果两种疗法都被证明部分有效，则为未来的联合疗法提供了可能性。我们提出BDNF的基因传递是因为需要将这种蛋白质直接输送到大脑中，并在一段时间内维持其传递。在建议的 根据工作计划，我们将在GMP设施中制造腺相关病毒血清2型(AAV2)载体，表达人BDNF，然后使用这种临床级材料在两个物种(大鼠和灵长类动物)上进行IND使能研究。此外，我们将利用MR引导的实时成像技术，产生准确靶向AAV2-BDNF并将其输送到灵长类内嗅觉皮质的专业知识。将实现以下目标：目标1：生产用于IND安全性/毒性/剂量研究的AAV2-BDNF。目的2：利用对流增强传递和实时MR引导，优化AAV2-BDNF基因在非人灵长类动物内嗅皮层的传递。目的3：在啮齿动物和非人灵长类动物中进行安全性/毒性/剂量/生物分布研究。目标4：起草并提交IND申请。相关性：这项工作的成功完成将导致一种防止细胞丢失和刺激神经功能的新方法在临床上转化为一种常见的、严重的和致残的神经退行性疾病。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common neurodegenerative disorder, afflicting 5 million people in the U.S. alone. This U grant application will support studies leading to the filing of an Investigational New Drug (IND) application to the FDA for Brain-Derived Neurotrophic Factor (BDNF) gene delivery in AD. We have completed proof-of-concept studies in mice, rats and non-human primates, demonstrating that BDNF prevents entorhinal cortical neuronal cell loss, enhances synaptic markers, reverses molecular and biochemical features associated with AD, and improves learning and memory. These effects extend into the hippocampus, thereby treating key memory circuitry of the brain. Importantly, this approach provides a much-needed alternative to amyloid-modifying therapeutics currently under development, providing future possibilities for combined therapies if both prove to be partly effective. We propose gene delivery of BDNF because of the need to administer this protein directly into the brain and sustain its delivery over time. In the proposed work plan, we will manufacture adeno-associated virus serotype 2 (AAV2) vectors expressing human BDNF at a GMP facility, then use this clinical-grade material to perform IND-enabling studies in two species (rat and primates). In addition, we will generate expertise in accurately targeting and delivering AAV2-BDNF to the primate entorhinal cortex using real-time, MR-guided imaging. The following aims will be performed: Aim 1: Produce AAV2-BDNF for IND-enabling safety/toxicity/dosing studies. Aim 2: Optimize AAV2-BDNF gene delivery to the entorhinal cortex in non-human primates using convection-enhanced delivery and real-time MR guidance. Aim 3: Safety/toxicity/dosing/biodistribution studies in rodents and non-human primates. Aim 4: Draft and Submit an IND Application. Relevance: Successful completion of this work will lead to clinical translation of a new approach to prevent cell loss and stimulate neural function in a common, severe and disabling neurodegenerative disorder.